Overproduction of superoxide by mitochondria has been demonstrated to be common to various pathways of hypergylcemic damage. Normalizing superoxide production, by supplemental superoxide dismutase e.g., eliminates the increases in advanced glycation end-products, protein kinase C activity, sorbitol concentration, and hexosamine pathway flux. It has therefore been proposed that supplemental antioxidants which interrupt the overproduction of superoxide should have therapeutic value against a wide spectrum of diabetic complications, including glomerulosclerosis, multifocal axonal degeneration, retinal ischemia, etc. While copious in vitro studies on both natural antioxidants (Vitamin E, a-Lipoic Acid, etc.) and synthetic antioxidants (ebselen, supoeroxide dismutatse mimetics, etc.) have demonstrated the ability to scavenge reactive oxygen species, clinical studies using supplemental natural antioxidants are far less conclusive. There are needs for both additional testing of antioxidants in cell cultures under hyperglycemic conditions and new antioxidant molecules that catalytically remove superoxide rather than merely scavenge one superoxide molecule per antioxidant molecule. Recently, a new class of synthetic antioxidants has been shown to be exceedingly effective at preventing mortality in mouse models of other disorders arising from increased oxidative stress. It is believed that the effectiveness of these new antioxidants arises from both a favorable cellular distribution and a catalytic mechanism for the deactivation of superoxide. This project will determine whether members of this class of antioxidants can extend their previous successes to afford protection of cells during hyperglycemic conditions, as well as to confer their benefits for retarding the microvascular complications arising from streptozotocin-induced diabetes in rats. The significance of the proposed work lies in the development of a new class of potent antioxidants suitable for mitigating the debilitating complications associated with diabetes. As diabetes is expected to affect over 17 million people in the USA alone by 2010, the impact of a sufficiently potent antioxidant that prevents or drastically reduces the complications arising from diabetes would have a broad impact on public health. [unreadable] [unreadable] [unreadable]